Process for the separation of a mixture of enantiomers

ABSTRACT

A diastereomer complex obtained via a process for the separation of enantiomers is disclosed, wherein separation can be rapidly effected such that enantiomers are obtained with high e.e. values. The process permits the separation of mixtures of enantiomers in which more than one resolving agent is used, of which at least one resolving agent is optically active, and which yields a diastereomer complex containing at least two resolving agents in optically active form. The process provides for, inter alia, a diastereomer complex having at least three compounds of which at least two compounds are resolving agents in optically active form, and at least one compound is an enantiomer in optically active form. Also provided is a diastereomer complex having at least three compounds of which at least one compound is a resolving agent in optically active form, and at least two compounds which are enantiomers in optically active form.

[0001] The invention relates to a process for the separation of amixture of enantiomers.

[0002] Mixtures of enantiomers are obtained, for instance, in reactionsthat do not, or only to a small extent, proceed stereoselectively and inreactions in which there is no complete inversion or retention. Thephysical properties of enantiomers, such as boiling point, melting pointand the like, are the same, so that a mixture of enantiomers cannot beseparated using the customary separation techniques. In one of themethods for the separation of mixtures of enantiomers, for instanceracemic mixtures, an optically active resolving agent is used to convertboth enantiomers into the corresponding diastereomers. As the physicalproperties of these diastereomers do differ, the diastereomers can, atany rate in principle, subsequently be separated by, for instance,crystallization or chromatography, both diastereomers being obtained insubstantially chemically pure and optically enriched form. Thediastereomer can in a third step again be separated into thecorresponding, optically enriched enantiomer and the optically activeresolving agent. Several processes and optically active resolving agentsfor the separation of enantiomers are, for instance, extensivelydescribed in “Stereochemistry of Organic Compounds” by E. L. Eliel andS. H. Wilen (Wiley Interscience, 1994).

[0003] However, it is common knowledge that finding the right resolvingagent for the separation of mixtures of enantiomers by crystallizationof a mixture of diastereomers is in practice a laborious and highlytime-consuming process, for a correct choice of the resolving agentcannot in advance be made, not even when applying advanced techniquessuch as, for instance, computer simulations or X-ray diffraction, andthus has to be found by trial and error for each mixture of enantiomersanew. This implies that for the separation of enantiomers viadiastereomers often many experiments have to be conducted, while theindividual experiments may take a long time on account of tediouscrystallization. Moreover, in not nearly all the cases is a suitableresolving agent found. It will therefore be clear that the search for agood resolving agent for the separation of mixtures of enantiomers of acompound and the conditions under which good results are obtained is atime-consuming matter and the chance of success is unpredictable.

[0004] The subject invention therefore aims to provide a process bywhich a separation of enantiomers can be effected rapidly and with ahigh chance of success and by which the desired enantiomer is obtainedwith a high e.e.

[0005] According to the invention this is among other things achieved bymeans of a process for the separation of mixtures of enantiomers inwhich more than one resolving agent is used, of which at least oneresolving agent is optically active, and which yields a diastereomercomplex that contains at least two resolving agents in optically activeform. It has been found that with the process according to the inventionmore often than in resolutions with a single resolving agent, directly acrystalline product is obtained instead of an oil, so that immediatelythe result of the experiment is known. Subsequent experiments canconsequently be done in a shorter period of time. Moreover, the processaccording to the invention allows testing of several resolving agentsand/or mixtures of enantiomers in one single experiment, so that theprocess according to the invention also allows rapid selection ofsuitable resolving agents. In addition, it has been found that in manycases the enantiomeric excess (e.e.) of the desired resolved enantiomeris higher when more than one resolving agent is used than when use ismade of a single resolving agent. Furthermore it has been found thatmixtures of enantiomers, which themselves cannot be resolved using acertain resolving agent, could be resolved when they were applied incombination with mixtures of enantiomers of similar structure.

[0006] According to the invention it is also possible to separate amixture of enantiomer mixtures, that is, a mixture of two or moredifferent chemical compounds in which both enantiomers of each compoundoccur, into substantially optically active enantiomers using one or moreresolving agents,-of which at least one resolving agent is opticallyactive. This is elucidated with reference to the following example, inwhich only one resolving agent is used: A mixture of the enantiomers of,for instance, compounds A, B and C (the mixture therefore contains 3mixtures of enantiomers: 3 pairs of two enantiomers each) is separatedinto a mixture containing optically enriched enantiomers of compounds A,B and C, use being made of only a single optically active resolvingagent. Of this second mixture subsequently the components A, B and C areseparated from the resolving agent. After this, the components A, B andC are separated by means of the customary separation techniques. Ofcourse, it is also possible to use a combination of different resolvingagents. This way, in a single experiment many combinations can berapidly tested.

[0007] The invention relates among other things to a diastereomercomplex, for instance a salt, comprising at least three compounds ofwhich at least one compound is a resolving agent in optically activeform and at least one compound is an enantiomer in optically activeform.

[0008] A diastereomer complex of one or more optically active resolvingagents and one or more enantiomers is understood to mean complexes inwhich the resolving agent(s) and the enantiomer(s) are bonded via one ormore non-covalent bonds, for instance van der Waals interactions,π-π-interactions, inclusion, ionogenic bonds, coordination bonds,hydrogen bonds and/or a combination of such bonds.

[0009] As resolving agent use can be made of any compound that issuitable for converting a mixture of enantiomers via precipitation intoa diastereomeric salt containing a mixture of enantiomers with a higherenantiomeric excess. The resolving agent may contain a metal, optionallywith the associated ligands. Preferably, as optically active resolvingagent use is made of a resolving agent with the highest possible e.e.,for instance an e.e. >95%, in particular >98%, more in particular >99%.

[0010] The term enantiomer in this context refers to the mixture ofenantiomers to be enriched. As mixture of enantiomers in principle allchiral compounds, in practice usually compounds containing at least oneasymmetrical carbon atom, can be used. The enantiomers can for instancebe compounds that contain at least an acid group, an amino group, ahydroxy group and/or a thiol group.

[0011] In principle a chemical compound that can be appropriately usedas a mixture of enantiomers to be separated with an appropriateresolving agent, also represents an appropriate resolvent agent to beused in the separation of a mixture of enantiomers.

[0012] In the framework of this invention the term mixture ofenantiomers means a mixture of the enantiomers of an optically activecompound in any ratio.

[0013] Naturally, in the framework of this invention the same holds withrespect to the separation of a mixture of enantiomers which already hasa certain enantiomeric excess as for racemic mixtures.

[0014] In a particularly suitable embodiment the mixtures of enantiomersare separated via salt formation. Examples of mixtures of enantiomersthat can suitably be separated via salt formation are acids, and basesin particular carboxylic acids, phosphoric acids, sulphonic acids,phosphinic acids, sulphinic acids, amines, acidic alcohols, amino acids,amino alcohols and acidic thiols.

[0015] Other examples of ways in which mixtures of enantiomers cansuitably be separated according to the invention are separations viainclusion compounds, for which in principle any chiral compound formingan inclusion compound can be used, or separation via metal complexes,for instance as described in J. A. Gladysz & B. J. Boone, Angew. Chem.Int. Ed. Engl. 36, p. 576-577, 1997.

[0016] As an example of a possible use of the process according to theinvention, the invention will now be elucidated with reference to theseparation of a racemic mixture of an amine using at least two opticallyactive acids or using at least one optically active acid and anon-optically active acid. A first commercially interesting use of theprocess according to the invention is the screening of resolving agents.In practice this is usually done at lab scale, with various acids, forinstance 2-20, in particular 2-12, more in particular 2-6,simultaneously being used as resolving agents. The combination of acidsfound in the complex precipitated usually offers the best prospects of agood result, it probably being possible in a number of cases to leaveout acids that are found in the complex in small amounts. Of course itis also possible that only one resolving agent, in this specific caseone acid, is found in the complex. In that case the resolving agentpreferably used will contain only one component.

[0017] The acids that upon screening at lab scale are selected maysubsequently be used as agent in the form of a mixture of at least two,for instance 2-6, in particular 2-3 acids in the separation of a racemicmixture of the amine on an industrial scale. An optically active amineand a mixture of at least 2 acids are obtained from the resultingdiastereomer mixture of salts.

[0018] Preferably, the resolving agents are of the same type, forinstance resolving agents within a certain group. Examples of groups ofresolving agents that can suitably be used in the process according tothe invention are:

[0019] Substituted phosphoric acids, for example phosphoric acids offormula S1:

[0020] where R₁ and R₂ each independently represent H, an alkyl group oran aryl group;

[0021] Optically active substituted tartaric acids, for instancetartaric acids of formula S2:

[0022] where R₁ and R₂ are as defined above;

[0023] Substituted α-hydroxycarboxylic acids, for instance mandelicacids of formula S3;

[0024] where R₁ and R₂ are as defined above;

[0025] N-acylamino acids, substituted or not, for instance N-acylaminoacids of formula S4:

[0026] where R₃ has a fixed meaning within a group, chosen from an alkylgroup or an aryl group, and R₄ represents an aryl group, for instance anR₁ and R₂ substituted phenyl group with R₁ and R₂ as defined above, oran alkyl group, for instance an amino acid radical as occurring innatural amino acids, or where R₄ has a fixed meaning within a group,chosen from an aryl group, for instance an R₁ and R₂ substituted phenylgroup with R₁ and R₂ as defined above, or an alkyl group, for instancean amino acid radical of natural amino acids, and R₃ represents an alkylgroup or an aryl group.

[0027] A special example is acylated protein hydrolysate. or of formulaS5 (N-benzyloxycarbonyl amino acids):

[0028] where R₄ is as defined above;

[0029] N-carbamoyl amino acids, substituted or not, for instanceN-carbamoyl amino acids of formula S6:

[0030] where R₄ is as defined above. A special example is carbamoylatedprotein hydrolysate;

[0031] Substituted phenalkylamines, for instance phenalkylamines offormula S7:

[0032] where R₁ and R₂ may vary within a group as defined above and R₅has a fixed meaning, chosen from alkyl, or R₁ and R₂ are fixed choicesfrom the groups as defined above and R₅ varies within the alkyl group;

[0033] Amino acid amides, substituted or not, for instance amino acidamides of formula S8:

[0034] where R4 is as defined above, and R6 and R7 are chosenindependently of each other from H and alkyl;

[0035] Substituted N-glucosamines, for instance N-glucosamines offormula S9:

[0036] where R₅ is as defined above;

[0037] Aryloxypropionic acids, for instance aryloxypropionic acids offormula S10:

[0038] where R₁ and R₂ are as defined above;

[0039] Optically active ethers of tartaric acids, for instance ethers offormula S11:

[0040] where R₈ is preferably methyl or benzyl;

[0041] optically active acetals of tartaric acids, for instance acetalsof formula S12:

[0042] where R₃ is as defined above and R₃′ independently represents thesame groups and is not equal to R₃;

[0043] optically active alkanoylesters of tartaric acids, for instanceof formula S13:

[0044] where R₅ is as defined above;

[0045] phenylaminopropane diols, for instance of formula S14:

[0046] where R₁ and R₂ are as defined above.

[0047] The substituents R_(i) with i=1-8 preferably contain 1-30,particularly 1-20 C-atoms and may optionally be substituted with analkyl group, alkoxy group, carboxyl group, alkoxycarbonyl group, aminogroup, nitro group, thio group, thioalkyl group, nitrile group, hydroxygroup, acyl group or halogen.

[0048] Examples of suitable mixtures of enantiomers are:

[0049] α-amino acids and their derivatives with as formula (E1):

[0050] where:

[0051] R₄ is as defined above

[0052] R₆ and R₇ are as defined above

[0053] R₉ stands for OH, alkoxy, NH₂

[0054] R₁₀ stands for H, alkyl and aryl

[0055] and R₄ is not the same as R₁₀

[0056] α-aminonitriles, for instance of formula (E2):

[0057] where R₄, R₆, R₇ and R₁₀ are as defined above;

[0058] β-amino acids (and derivatives) for instance of formula (E3)

[0059] where R₄, R₆, R₇ and R₈ are as defined above. phenalkylamines,for instance of formula E4:

[0060] where R₁, R₂, R₅, R₆ and R₇ are as defined above; piperazines,for instance piperazines of formula E5:

[0061] where R₁₀ is as defined above and R₁₁ and R₁₂ independentlyrepresent an alkyl group, aryl group or COR₉ group;

[0062] piperidines, for instance piperidines of formula E6:

[0063] where R₁₀ is as defined above and R₁₃ and R₁₄ each independentlyrepresent R₁₁, OH or an alkoxy group; pyrrolidines, for instancepyrrolidines of formula E7:

[0064] where R₁₀, R₁₃ and R₁₄ are as defined above;

[0065] morpholines, for instance morpholines of formula E8:

[0066] where R₁₀, R₁₁, and R₁₂ are as defined above;

[0067] diamines, for instance diamines of formula E9:

[0068] where m and n each independently is 0-5 and where R₁₁ is asdefined above and R₆′ and R₇′ independently thereof represent the samegroups as R₆ and R₇;

[0069] ephedrines, for instance ephedrines of formula E10:

[0070] where R₁, R₂, R₆ and R₇ are as defined above.

[0071] amino alcohols or amino ethers, for instance of formula E11a,E11b or E11c:

[0072] where n is 0-10, R₁₅=H or alkyl and where R₁₀′ independentlythereof represents the same groups as R₁₀ and R₆, R₇, R₁₀, R₃ and R₃′are as defined above;

[0073] 1-(2-naphthyl)alkylamines, for instance 1-(2-naphthyl)alkylaminesof formula E1-2:

[0074] where R₁, R₂, R₅, R₆ en R₇ are as defined above;

[0075] aliphatic amines, for instance aliphatic amines of formula E13:

[0076] where R₆, R₇, and R₁₀ are as defined above, and R₁₀′ and R₁₀″ arechosen from the same group as R₁₀ and are not the same as each other andas R₁₀;

[0077] phosphoric acids, for instance phosphoric acids of formula (E14):

[0078] where R₁ are R₂ as defined above;

[0079] carboxylic acids, for instance carboxylic acids of formula E15:

[0080] where R₃ en R₃′ are as defined above;

[0081] substituted butane dicarboxylic acids for instance of formula(E16):

[0082] where R₃ en R₄ are as defined above;

[0083] aromatic or aliphatic hydroxycarboxylic acids or derivativesthereof, in particular substituted mandelic acids, for instanceα-hydroxycarboxylic acids of formula E17:

[0084] where R₁₀, R₁₀′ and R₁₅ are as defined above and R₁₀ and R₁₀′ aredifferent;

[0085] sulphonic acids, in particular (substituted) camphor-sulphonicacids or (substituted) 1-phenylalkane-sulphonic acids of formula E18:

[0086] where R₁, R₂ and R₃ are as defined above; 2-aryloxyalkanoicacids, in particular 2-aryloxypropionic acids of formula E19:

[0087] where R₁ and R₂ are as defined above; biaryl biacids, inparticular biaryl bicarboxylic acids of formula E20:

[0088] where R₁ and R₂ are as defined above and R₁′ and R₂′ areindependently thereof chosen from the same groups as R₁ and R₂;

[0089] substituted bi(hetero)aryldifosfinic oxides,

[0090] particularly binaphthalene difosfinic oxides of formula E21:

[0091] wherein R₁ and R₂ are as defined above and are situatedarbitrarily on the naphthalene skeleton, and Ar represents a(hetero)aryl group.

[0092] The substituents Ri with i =1-15 and Ar preferably contain 1-30,in particular 1-20 C-atoms and may or may not be substituted with analkyl group, alkoxy group, carboxyl group, alkoxycarbonyl group, aminogroup, nitro group, thio group, thioalkyl group, nitrile group, hydroxygroup, acyl group or halogen.

[0093] As is known to one skilled in the art, during crystallizationinclusion of one or more solvent molecules may also take place. Thediastereomer complex according to the invention may therefore alsocontain one or more molecules of a solvent. The ratio of the resolvingagents to each other may vary within a wide range, with, in the case ofsalt formation, the sum of the acid groups and the sum of the basicgroups in the complex having to be equal. It has, surprisingly, beenfound that after one or two recrystallizations the diastereomersaccording to the invention remain constant as regards the ratio of theresolving agents in the diastereomer upon further recrystallizations.

[0094] This proves that the widespread ratio of resolving agents that isfound is not the result of simple inclusion, for instance due to toorapid crystallization.

[0095] The invention also relates to an agent for separating a mixtureof enantiomers, the agent comprising at least two resolving agents ofwhich at least one is optically active. Preferably, the agent containsat least two resolving agents of the same type.

[0096] The invention also relates to a process for separating a mixtureof enantiomers. This process is characterized in that the mixture ofenantiomers is contacted in a suitable solvent with at least tworesolving agents, at least one of which is optically active, yieldingthe diastereomer complex as described above. The sequence in which thistakes place is not critical. In the process use is made of standardprocedures and conditions that are generally known for separation ofenantiomers via the formation of diastereomers. One skilled in the-artcan simply find out which principles and methods used for optimizationof classical resolution processes can also be applied to the processaccording to the subject invention. One option is, for instance, toreplace a portion of the resolution acids or bases with mineral acids orbases in order to optimize the use of the expensive resolving agents.Also, the result of the resolution may be strongly dependent on themolar ratio of resolving agent to the racemate. Such ratio may forinstance be varied between 0,5 and 2.

[0097] Although this is not preferred, it is also possible to resolve amixture of enantiomers by first adding one or more resolving agent(s)and, when no crystallization of a diastereomer takes place, add one ormore further resolving agent(s), etc. This can be done by, for instance,adding 2-21, preferably 2-13 and in particular 2-7 resolving agents. Itwill be clear to one skilled in the art that this process is moretime-consuming, for which reason the resolving agents are preferablyadded simultaneously, certainly at lab scale.

[0098] On an industrial scale the addition of the resolving agents willbe chosen so that the crystallization is controllable and, for instance,no crystallization takes place at undesirable places in the installationand also the heat development per unit of time remains controllable. Toachieve this, dosing in time of the combination of resolving agents canbe adapted. Optionally, the resolving agents are added one after theother. The optimum way of adding the resolving agents can simply bedetermined by one skilled in the art.

[0099] The optically active resolving agents according to the inventionpreferably have an e.e. larger than 95%, in particularly larger than98%, more in particular larger than 99%.

[0100] It has, surprisingly, also been found that when several opticallyactive resolving agents are applied, these need not necessarily have thesame absolute configuration. It has, for instance, been found that whenuse is made of three resolving agents A, B and C, a separation waspossible both when A and B had, for instance, the S-configuration and Cthe R-configuration, and when A, B and C all had the S-configuration.The complex formed in both cases contained A and B as well as C, C inboth cases having a different configuration. This may be useful in thecases where only one enantiomer of the relevant resolving agent is wellobtainable.

[0101] Preferably, substantially only the diastereomer complex accordingto the invention crystallizes out with the highest possible e.e. of theseparate compounds, following which it can be isolated using customarytechniques. This may also involve chemical purification of thediastereomer complex. The process according to the invention cantherefore also be applied to effect chemical purification of the mixtureof enantiomers.

[0102] The conversion of the above-mentioned diastereomer complex to theenantiomers present in it is carried out in ways that are generallyknown to one skilled in the art, for instance by acid or base treatmentfollowed by extraction, distillation or chromatography.

[0103] From practice it is known that the use of a mixture of two ormore different solvents in crystallizations may sometimes give betterresults. If a mixture of solvents is used, this mixture for instanceconsists of 2-5 different solvents, and in particular of 2-3. Theprocess according to the subject invention can therefore also be carriedout using a mixture of two or more different solvents.

[0104] The invention will be elucidated on the basis of examples.

[0105] Definitions and Syntheses

[0106] P-mix Phencyphos, P1, (1,3,2-dioxaphosphorinane,-5,5-dimethyl-4-phenyl-2-hydroxy-2- oxide) Chlocyphos, P2,(1,3,2-dioxaphosphorinane,-5,5- dimethyl-4-(2′-chlorophenyl)-2-hydroxy-2-oxide) Anicyphos, P3, (1,3,2-dioxaphosphorinane,-5,5-dimethyl-4-(2′-methoxyphenyl)-2- hydroxy-2-oxide)

[0107] were prepared and resolved according to Ten Hoeve and Wijnberg,U.S. Pat. No. 4,814,477.

[0108] W-mix

[0109] W1, Dibenzoyltartaric acid,

[0110] W2, Di-p-toluoyltartaric acid were obtained from Aldrich.

[0111] W3, Di-p-anisoyltartaric acid was prepared and resolved followingliterature procedures.

[0112] α-mix

[0113] A1, Mandelic acid was obtained from Aldrich,

[0114] A2, p-methylmandelic acid

[0115] A3, p-fluoromandelic acid

[0116] were prepared and resolved following literature procedures.

[0117] Other mandelic acid analogs, p-methoxymandelic acid,p-bromomandelic acid and p-chloromandelic acid were prepared andresolved following literature procedures.

[0118] PEA I-mix

[0119] p-Br-PEA, p-Br-phenethylamine was prepared according to: J.A.C.S.105, 1578-84 (1983) via Leuckhart synthesis from commercially availablep-Br-acetophenone (Aldrich). Resolution see Example I.3; Table 1.

[0120] p-Cl-PEA, p-Cl-phenethylamine was prepared as above fromp-Cl-acetophenone (Aldrich). Resolution see Example I.6 and I.7; Table1.

[0121] p-CH₃-PEA, p-CH₃-phenethylamine was prepared as above fromp-CH₃-acetophenone (Aldrich). Resolution see Example I.4 and I.5; Table1.

[0122] Resolution of rac. PEA I-mix see E; Examples IX-XI.

[0123] PEA II-mix

[0124] PEA, phenethylamine (Aldrich),

[0125] p-NO₂-PEA, p-NO₂-phenethylamine and

[0126] o-NO₂-PEA, o-NO₂-phenethylamine

[0127] p-NO₂-PEA and o-NO₂-PEA were prepared as a 1:1 mixture asdescribed in the literature from optically pure PEA (Aldrich).

[0128] The mixture is applied with a ratio

[0129] PEA: p-NO₂-PEA: o-NO₂-PEA=1:1:1

[0130] PEA IIA-mix,

[0131] p-NO₂-PEA and o-NO₂-PEA as 1:1 mixture.

[0132] PEA IIB-mix

[0133] PEA and p-NO₂-PEA as 1:1 mixture

[0134] Pure p-NO₂-PEA was obtained via crystallization of the

[0135] HCl salt.

[0136] PEA III-mix

[0137] m-MeO-PEA, m-CH₃O-phenethylamine

[0138] m-Cl-PEA, m-Cl-phenethylamine

[0139] m-Br-PEA, m-Br-phenethylamine

[0140] were synthesized following the same procedure used for thesynthesis of the para analogues.

[0141] Resolution or rac. PEA III-mix see E; Example XII

[0142] Other PEA analogs (from the o-, m-, and p-series) weresynthesized following the known procedure.

[0143] BA I-mix

[0144] α-Me-BA, α-methylbenzylamine (Aldrich);

[0145] α-Et-BA, α-ethylbenzylamine and

[0146] α-iP-BA, α-isopropylbenzylamine

[0147] were synthesized following literature procedures.

[0148] Resolution of BA I-mix see E; Example XIII

[0149] A. Small Scale Resolution of Amines with the P-mix, W-mix andα-mix

EXAMPLE I

[0150] General Procedure:

[0151] To a solution of the racemic (rac.) amine (1-10 mmol) to beresolved in a solvent as indicated in table 1 was added onemolequivalent of the P-, W- or α-mixture, each as a 1:1:1 mixture of itscomponents.

[0152] The resulting mixture was heated to reflux (in some cases a clearsolution was not obtained) and the mixture was allowed to cool to roomtemperature (RT). The solid was collected by suction, dried and analyzedby ¹H-NMR (200 MHz, DMSO(dimethylsulphoxide)-d6).

[0153] The enantiomeric excess (e.e.) of the amines was determined bychiral HPLC after isolating the free amine from the salt by treatmentwith 10% NaOH solution and extraction with organic solvent. Columns usedare listed below together with their indication number in Table 1.

[0154] Chiral HPLC Columns:

[0155] 1: Crownpak Cr

[0156] 2: Chiralpak AD

[0157] 3: Chiralcel OD

[0158] 4: Chiralcel OB

[0159] 5: Chiralcel OJ

[0160] 6: R,R Whelk

[0161] 7: Ultron ES OVM

[0162] The salt was recrystallized from the indicated solvent(s) andagain analyzed; the number of recrystallizations is indicated in table Itogether with the solvent. On small scale the yields were notdetermined. The results of the small scale resolutions are summarized inTable 1, wherein the indication of the solvent by A, B, C . . . . .stands for:

[0163] A: 2-butanone

[0164] B: ethanol (EtOH)

[0165] C: 2-propanol

[0166] D: methanol (MeOH)

[0167] E: ethylacetate (EtOAc)

[0168] F: toluene

[0169] G: water

[0170] The ratio mix P1/P2/P3 refers to the molar ratio of compoundP1:P2:P3 present in the solid. TABLE 1 no. of ratio mix entry mixrecryst. ee P1/P2/P3 ref. amine (−) solvent (solvent) (%) HPLC etc. 1p-MeO-phenethylamine P A/B 1 65 1 7:9:0 2 W A/B 1 56 1 0:1:2 3p-Br-phenethylamine A A 1 96 1 1:5:0 4 p-Me-phenethylamine W B 1 (G) 501 1:1:1 5 A C 1 96 1 1:5:0 6 p-Cl-phenethylamine P C 1 (B) 92 1 3:3:4 7A C 1 (D) 94 1 1:5:0 8 o-Cl-phenethylamine P A 1 (A/B)  99** 1 20:0:1 9W B 2 95 1 1:5:20 10 A* A 1 75 1 1:1 11 o-Br-phenethylamine A* A/C 1 (C)90 1 1:1 12 o-Me-phenethylamine P A 0 (D) 51 2**** 1:0:0 13 W A/C 1 (D)10 2**** 1:3:2 14 A* A/C 1 90 2**** 1:1 15 m-MeO-phenethylamine P A/C 1(D) 80 1 5:4:1 16 A* A/C 1 94 1 1:10 17 m-Me-phenethylamine P A/C 1 (C) 99** 1 5:5:1 18 A F 1 99 1 2:5:2 19 m-Cl-phenethylamine A* A/C 1 (C) 991 1:4 20 m-Br-phenethylamine P A/C 1 (D) 50 1 3:3:1 21m-Br-phenethylamine A* A/C 1 (C) 99 1 1:4 22 cis-2-phenylhydroxy- W C 199 2 5:1:1 piperidine 23 α-methylphenylalanine P B 1 92 1 4:1:2 24α-methylphenylalanine P A 1 99 1 2:1:3 amide 25 W A 1 33 1 1:8:6 265-ethyl-5-methyl-2- P A 1 (A/D) 98 1 4:1:0 fenyl-4-imidazolidinone (cis& trans) 27 3-quinuclidinol P A/D 1 ca. 2 1:1:2   66*** 283-quinuclidinol-benzoic W D 1 (D/G)  98** 2 1:10:4 ester 29N-methyl-2-allyl-2-(3,4- P A 1 75 2 5:1:3 dichlorophenyl)- ethylamine 30N-ethyl-2-aminoethyl- P A 1 (A/C)   89*** 2 4:1:0 pyrrolidine 31α-ethynylbenzylamine P C 2 95 2 6:1:1 32 W A/C 1 90 4 2:1:4 33trans-N-benzyl-3,4- W C 1 97 2 6:1:1 diphenylpyrrolidine 34trans-3,4-diphenyl- W A 1 (A/D) 99 2**** 1:3:3 pyrrolidine 35 P A/D 1(A/D) 95 2**** 2:1:1 36 p-hydroxyphenyl-glycine P B/G 1 95 1 1:2:3 37p-fluorophenylglycine P A 1 98 2 20:2:1 nitrile 38 W A 1 35 2 n.d. 39p-fluorophenylglycine P A 1 (B) 94 1 15:3:2 methylester 403-ethylmorfoline W B 2  96** 2**** 0:2:1 41 2-aminobutanol A* A 1 >98  2**** 2:3 42 α-isopropylbenzylamine P A 1 (C) 80 1 20:1:1 43α-ethylbenzylamine P A 1 (C) 72 1 1:1:1

EXAMPLES OF PREPARATIVE RESOLUTIONS EXAMPLE II

[0171] The experiment of example I.8 was repeated on a larger scale.

[0172] To a solution of rac. o-Cl-PEA (57.5 g; 366 mmol) in 800 ml EtOHwas added a mixture of (−)-phencyphos (84 g) and (−)-anicyphos (4 g).The mixture was heated at reflux (no clear solution) and cooled to RT.The solid was collected and recrystallized from 1.5 1 EtOH. Yield 42 g(HPLC 9096 e.e.). This salt was recrystallized from 650 ml EtOH toafford 22.1 g (15%) salt with >99% e.e.

EXAMPLE III

[0173] The experiment of example I.17 was repeated on a larger scale.

[0174] 20.5 g (150 mmole) racemic 3-methylphenylethylamine was dissolvedin 900 ml 2-propanol and 13.35 g (50 mmole) (−)-chlocyphos, 13.6 g (50mmole) (−)-anicyphos and 12.1 g (50 mmole) (−)-phencyphos were added.Heated to reflux and after addition of 50 ml MeOH a clear solution wasobtained. The heating was stopped and the solution was stirred for 18hours. The salt was collected, rinsed with 2-propanol and wet salt (HPLC78% e.e.) recrystallized from 500 ml 2-propanol and 120 ml MeOH,yielding 11.6 g (18%) salt with 9696 e.e. (HPLC).

EXAMPLE IV

[0175] The experiment of example I.28 was repeated on a larger scale.

[0176] To a solution of 3-quinuclidinol-benzoate (30 g, 126 mmol) inMeOH (1,2 1) was added a mixture of Di-p-anisoyl-L-tartaric acid (17 g,34 mmol), Di-p-toluoyl-L-tartaric acid (30.6 g, 76 mmol) andDibenzoyl-L-tartaric acid (4.4 g, 11 mmol). The mixture was heated toreflux and cooled to RT. The resulting salt was heated at reflux inMeOH/water (8:2) (1 1) for 10 min. and cooled to RT. The salt wascollected and treated with 10% NH₄0H/TBME. The quinuclidinolbenzoate (12g, 40%) was enantiomerically pure (>98%) by HPLC.

[0177] The benzoate was converted to enantiomerically pure(+)-(S)-quinuclidinol by treatment with 10% HCl (reflux, 16 hours).

EXAMPLE V

[0178] The experiment of Example I.40 was repeated on a larger scale.4.55 g (30 mmole) racemic 2-ethylmorpholine was dissolved in 100 ml EtOH(96%) and a solution of 3.76 g (10 mmole)(−)-dibenzoyltartaric acid, 4.0g (10 mmole)(−)ditoluoyltartaric acid and 4.36 g (10 mmole)(−)-dianisoyltartaric acid in 100 ml EtOH (96%) was added at once.Crystallization started within 30 minutes and stirring was continued foranother hour. The salt was collected, rinsed with EtOH (HPLC 70% e.e.)and recrystallized from 100 ml EtOH before complete drying. This yielded2.6 g (30%) salt with 88% e.e. Another recrystallization from EtOHyielded 1.6 g (19%) salt with 96% e.e.

EXAMPLE VI

[0179] Resolution of DL-3-amino-3-phenylpropionic acid with P-mix

[0180] A mixture of racemic 3-amino-3-phenylpropionic acid (990 mg, 6mmol) and (−)P-mix (2 mmol each) in 15 ml 2-butanone was heated toreflux. The clear solution was allowed to cool to room temperature.After stirring for 1 hour at room temperature the solid was collected bysuction, washed with 1 ml 2-butanone and dried, yielding 804 mg salt.The solid was analyzed by ¹H-NMR, showing a mixture of phencyphos,chlocyphos and anicyphos in a molar ratio of 5:4:1.

[0181] An enantiomeric excess of >98% was determined by chiral HPLC(Crownpack CR (+)).

[0182] C. Small Scale Resolution of Acids with the PEA-mixes

EXAMPLE VII

[0183] General Procedure:

[0184] To a solution of the racemic acid (1-10 mmol) in the solvent asindicated(see list) was added one molequivalent of the PEA mixture eachas a 1:1(:1) mixture of its components. Solvents:

[0185] A: 2-butanone

[0186] B: ethanol (EtOH)

[0187] C: 2-propanol

[0188] D: methanol (MeOH)

[0189] E: ethylacetate (EtOAc)

[0190] F: toluene

[0191] G: water

[0192] The resulting mixture was heated to reflux (in some cases a clearsolution was not obtained) and the mixture was allowed to cool to roomtemperature (RT). The solid was collected by suction, dried and analyzedby ¹H-NMR (200 MHZ,DMSO-d6).

[0193] The enantiomeric excess (e.e.) of the amines was determined bychiral HPLC after isolating the free acid from the salt by treatmentwith 10% HCl solution and extraction with organic solvent. Columns usedare listed below:

[0194] Chiral HPLC Columns:

[0195] 1: Crownpak Cr

[0196] 2: Chiralpak AD

[0197] 3: Chiralcel OD

[0198] 4: Chiralcel OB

[0199] 5: Chiralcel OJ

[0200] 6: R,R Whelk

[0201] 7: Ultron ES OVM

[0202] The salt was recrystallized from the solvent(s) as indicated andagain analyzed. On small scale the yields were not determined. Theresults of the small scale resolutions are summarized in Table 2.

[0203] The ratio mix refers to the molar ratio of the compounds of themix present in the solid, in the sequence as given in the definition ofthe mixes. TABLE 2 no. entry mix recryst. ratio ref. acid (+) solvent(solvent) ee HPLC mix 1 p-Me mandelic acid PEA A 1 (B/D) 96 2 4:1 IIA 2PEA A/D 1 99 2 1:4 IIB 3 p-fluoro-mandelic acid PEA A 1 (A/D) 98 2 10:1IIA 4 PEA A 0 99 2 n.d. IIB 5 p-Br-mandelic acid PEA A 1 (A/D) 99 215:1:0 II 6 PEA A 1 99 2 n.d. I 7 p-Cl-mandelic acid PEA A 1 (A/D) >95  2 35:1:0 II 8 PEA A 1 93 2 n.d. I 9 m-Me-mandelic acid PEA A/C 0 67 2n.d. I 10 2-(p-Cl- PEA E 1 (E) 88 2 n.d. phenoxy)propionic acid I 113-chloro-iso-butyric PEA C 1 59 2 n.d. acid I 12 2-phenylbutyric acidPEA A 1 (A/C) 85 2 n.d. I 13 PEA A 1 90 2 4:1:0 II 142-(p-Br-phenyl)butyric PEA A 1 75 2 n.d. acid I 15 PEA A 1 (C) 95 21:0:0 II 16 phenylsuccinic acid PEA A 1 (A/D) 90 3 n.d. I 17benzylsuccinic acid PEA A 1 (C) 88 3 2:2:1 II 18 PEA* A 1 (C) 57 3 n.d.III

[0204] D. Resolution with a N-acyl-fenylalvcine-mix

EXAMPLE VIII

[0205] Resolution of cis-1-aminoindan-2-ol with N-acyl-phenylalycine Mix

[0206] 992 mg cis-1-aminoindan-2-ol and a mix ofN-benzoyl-D-phenylglycine, N-toluoyl-D-phenylglycine andN-p-anisoyl-D-phenylglycine (2 mmol each) in 20 ml toluene and 5 mlbutanone was heated to reflux and allowed to cool to room temperature.The solid was isolated, washed with 1 ml of toluene and dried. In thisway 380 mg salt was obtained.

[0207] HPLC analysis showed N-benzoyl phenylglycine, N-toluoylphenylglycine and N-anisoyl phenylglycine with a molar ratio of1:1.6:0.9.

[0208] The e.e. of (−)-cis-1-aminoindan-2-ol was 82% (chiral HPLC,Crownpack CR (−)).

[0209] Recrystallization of the salt from 5 ml toluene and 2 ml2-butanone gave 180 mg salt with N-benzoyl phenylglycine, N-toluoylphenylglycine and N-anisoyl phenylglycine in a molar ratio of 1:1.8:0.8.The e.e. of the (−)-cis-1-aminoindan-2-ol was 96%.

[0210] E. Resolution of Mixtures of Racemic (rac) Mixtures ofEnantiomers

EXAMPLE IX

[0211] Resolution of rac. PEA-I-mix with (R)-p-CH₃-mandelic Acid((R)-p-Me-MA)

[0212] To a mixture of rac. p-Br-PEA, p-Cl-PEA and p-Me-PEA (100 mmoleach) in 600 ml EtOH (96%) was added (R)-p-Me-MA (300 mmol, 50 g). Themixture was refluxed and allowed to cool to room temperature (RT). Thesolid was collected and recrystallized from EtOH (500 ml). The solid wascollected and dried. Yield 33 g (35%). The mixed salt contained of(R)-p-Br-PEA, (R)-p-Cl-PEA and (R)-p-Me-PEA in 1:1:1 ratio. The salt wastreated with 10% NaOH/TBME and the PEA I-mix was isolated as a slightlyyellow oil. HPLC analysis (1) showed all three amines with e.e. >98%.

EXAMPLE X

[0213] Resolution of rac. PEA I-mix with (S)-p-Me-mandelic acid and(S)-p-Br-mandelic Acid

[0214] To a mixture of rac. p-Br-PEA, p-Cl-PEA and p-Me-PEA (13 mmoleach) in 200 ml EtOH (96%) was added a mixture of (S)-p-Br-MA and(S)-p-Me-MA (20 mmol each)). The mixture was refluxed and allowed tocool to RT. The solid was collected and recrystallized from EtOH (100ml). The solid was collected and dried. Yield 6 g (43%). The mixed saltcontained (S)-p-Br-PEA, (S)-p-Cl-PEA and (S)-p-Me-PEA in 1:1:1 ratio andof (S)-p-Br-MA and (S)-p-Me-MA (1:1). The salt was treated with 10%NaOH/TBME and the PEA I-mix was isolated as a slightly yellow oil. HPLCanalysis (1) showed all three amines with e.e. >98%.

EXAMPLE XI

[0215] Resolution of rac. p-MeO-PEA in the Presence of rac. PEA-I-mixwith (R)-p-CH3-mandelic Acid

[0216] To a mixture of rac. p-MeO-PEA, p-Br-PEA, p-Cl-PEA and p-Me-PEA(10 mmol each) in 60 ml EtOH (96%) was added (R)-p-Me-MA (40 mmol 6,5g). The mixture was refluxed and allowed to cool to RT. The solid wascollected and recrystallized from EtOH (50 ml). The solid was collectedand dried. HPLC analysis (1) showed that the mixed salt consisted of allfour amines with a ratio of 3:52:30:13 respectively. The e.e. of allfour amines were >98%.

[0217] Note: p-MeO-PEA could not be resolved with the α-Mix but could beresolved in the presence of other PEA amines.

EXAMPLE XII

[0218] Resolution of rac. PEA III-mix

[0219] To a mixture of m-MeO-PEA, m-Cl-PEA, and m-Br-PEA (100 mmol each)in EtOH (600 ml) was added (S)-p-Me MA (45 g, 300 mmol). The mixture washeated to reflux and allowed to cool to RT overnight. The solid wascollected and dried, yield 34 g (38%). The salt was treated with 10NaOH/TBME and 16.8 g of the PEA III mix was isolated. HPLC analysis (1)showed a 2:4:4 ratio with an e.e. >98%.

Example XIII

[0220] Resolution of rac. BA I-mix

[0221] 50 g (0.33 mole) rac. α-isopropylbenzylamine, 45 g (0.33 mole)rac. α-ethylbenzylamine and 24.2 g (0.2 mole) S-(−)-α-methylbenzylaminewere dissolved in 1.5 1 IPA and 208 g (0.86 mole) (+)-Phencyphos wasadded. The mixture was heated to reflux and 1.0 1 EtOH was added to geta clear solution. The mixture was allowed to cool to room temperatureunder stirring for 18 hours, the salt was collected.

[0222] A sample of the mixture of resolved amines was liberated from thesalt and HPLC showed 90% e.e. for the two resolved amines. The salt wasrecrystallized from 1.2 1 EtOH, yielding 60 g (26%) salt with >98% e.e.for all 3 amines. The ratio of the amines was 4:6:1 (α-methyl; α-ethyl;α-isopropyl) as determined by GC (120° C.).

[0223] An experiment without S-(−)-α-methylbenzylamine added, yielded asalt with both other amines with 40% e.e. and a recrystallization gavean e.e. of 70%.

[0224] Separate resolution experiments with α-isopropylbenzylamine andα-ethylbenzylamine with (+)-phencyphos gave e.e.'s below 5%.

EXAMPLE XIV

[0225] Resolution of rac. anicyphos, chlocyphos and 2,4-dichlocyphoswith (−)-ephedrine

[0226] To a mixture of rac. anicyphos, chlocyphos and 2,4-dichlocyphos(1,3,2-dioxaphosphorinane-5,5-dimethyl-4(2′,4′-dichlorophenyl)-2-hydroxy-2-oxide)(10 mmol each) in 2-propanol (250 ml) was added (−)-ephedrine (30 mmol).The mixture was heated to reflux and allowed to cool to RT. The solidwas collected and recrystallized from 2-propanol. The mixed salt wastreated with 10% HCl for 30 min. and the solid collected. HPLC analysis(6) showed (+)-anicyphos, (+)-chlocyphos and (+)-2,4-dichlocyphos in aratio of 55:35:5 with e.e.'s >98%.

EXAMPLE XV

[0227] Resolution of rac. anicyphos, chlocyphis and 2,4-dichlocyphoswith (−)-p-hydroxyphenylglycine

[0228] To a mixture of rac. anicyphos, chlocyphos and 2,4-dichlocyphos(10 mmol each) in EtOH/water (8:2) was added (−)-p-hydroxyphenylglycine(30 mmol). The mixture was heated to reflux and allowed to cool to RT.The solid was collected and treated with 10% HCl for 30 min. The acidswere collected by suction. HPLC analysis (6) showed anicyphos,chlocyphos and 2,4-dichlocyphos in a ratio of 1:35:65 with e.e.'s 98%.

[0229] F. Resolution of a Racemate with a Mixture of Resolving Agents ofWhich Some are Racemic and Others Enantiomerically Sure.

EXAMPLE XVI

[0230] Resolution of rac. p-Br-PEA with p-Br-mandelic Acid and p-Me-MA

[0231] a) Using (S)-p-Br-Mandelic Acid and (S)-p-Me-MA.

[0232] To a mixture of rac. p-Br-PEA (2 g) in MeOH was added a mixtureof (S)-p-Br-mandelic acid and (S)-p-Me-MA (1 g each). The salt wascollected and analysed by ¹H-NMR (MA 1:1) and HPLC (1). The e.e. of theamine was 84%.

[0233] b) Using rac-p-Br-mandelic acid and (S)-p-Me-MA.

[0234] To a mixture of rac. p-Br-PEA (2 g) in MeOH was added a mixtureof rac. p-Br-MA and (S)-p-Me-MA (1 g each). The salt was collected andanalysed by ¹H-NMR (MA 3:4) and HPLC (1) and (2). The e.e. of the aminewas 90% and the e.e. of p-Br-MA 95%.

[0235] c) Using (S)-p-Br-mandelic Acid and rac. p-Me-MA

[0236] To a mixture of rac. p-Br-PEA (2 g) in MeOH was added a mixtureof (S)-p-Br-mandelic acid and rac. p-Me-MA (1 g each). The salt wascollected and analysed by ¹H-NMR (MA 4:3) and HPLC (1) and (2). The e.e.of the amine was 99% and the e.e. of p-Me-MA >95%.

EXAMPLE XVII

[0237] Resolution of p-Cl-PEA with the P-mix Containing RacemicPhencyphos

[0238] To a solution of rac. p-Cl-PEA in 2-butanone was added a mixtureof (−)-anicyphos, (−)-chlocyphos and rac. phencyphos (1 g each). Theresulting salt was recrystallized from EtOH and analysed by HPLC (1) and(6). The amine had an e.e. of 84% and the phencyphos an e.e. of 80-85%.

EXAMPLE XVIII

[0239] Resolution of Chlocyphos with (−)-ephedrine and (+)-phencyphos

[0240] To a solution of (−)-ephedrine (2.4 g) in 2-propanol (50 ml) wasadded (+)-phencyphos (1.75 g) and rac. chlocyphos (1.85 g). The mixturewas heated to reflux and allowed to cool to RT. The salt (3.31 g) wastreated with 10% KOH/toluene. The organic layer was acidified and thesolid analysed with HPLC (6). Both (+)-phencyphos and (+)-chlocyphoswere enantiomerically pure (>98%).

EXAMPLE XXI

[0241] Resolution of Phencyphos with (+)-ephedrine and (−)-chlocyphos

[0242] To a solution of (+)-ephedrine (2,6 g) in 2-propanol (70 ml) wasadded rac.-phencyphos (1.90 g) and (−)-chlocyphos (2,04 g). The mixturewas heated to reflux and allowed to cool to RT. The salt (2.78 g) wastreated with 10% KOH/toluene. The organic layer was acidified and thesolid analysed with HPLC (6). Both (−)-phencyphos and (−)-chlocyphoswere enantiomerically pure (>98%).

[0243] Note: Phencyphos could not be resolved with ephedrine but couldbe resolved with ephedrine in the presence of chlocyphos.

EXAMPLE XX

[0244] Resolution of rac. N-benzyl-3,4-bis-(p-methoxyphenyl)-pyrrolidinewith (−)-N-benzyl-3,4-diphenylpyrrolidine and(−)-di-(p-anisoyl)-tartaric Acid

[0245] To a mixture of rac.N-benzyl-3,4-bis-(p-methoxyphenyl)-pyrrolidine (1,2 g) and(−)-N-benzyl-3,4-diphenylpyrrolidine (1 g) in 2-butanone (50 ml) wasadded (−)-di-(p-anisoyl)-tartaric acid (2.4 g). The mixture was heatedto reflux and cooled to RT. The resulting salt was recrystallized twicefrom 2-butanone. HPLC analysis (2) showedN-benzyl-3,4-bis-(p-methoxyphenyl)-pyrrolidine and(−)-N-benzyl-3,4-diphenylpyrrolidine in a 1:10 ratio with an e.e. of 93%for N-benzyl-3,4-bis-(p-methoxyphenyl)-pyrrolidine.

[0246] Note: we have not been able to resolve this amine via resolutionwith a single resolving agent, nor using the P-mix or the W-mix in theabsence of N-benzyl-3,4-diphenylpyrrolidine.

[0247] G. Resolution of (a) Racemic Amine(s) with a Mixture ofEnantiomerically Pure Mandelic Acids and a Non Chiral Acid (PhenylaceticAcid)

EXAMPLE XXI

[0248] 1.35 (10 mmole) racemic p-CH₃-phenethylamine was dissolved in 25ml IPA and 500 mg (3.3 mmole) R-(−)-mandelic acid, 550 mg (3.3 mmole)R-(−)-p-CH₃-mandelic acid and 450 mg (3.3 mmole) phenylacetic wereadded. Under reflux a clear solution was obtained which was allowed tocool to room temperature and the salt was collected after 1 hour. ¹H NMRof the salt showed all 3 acids present and HPLC of the free amine showed82% e.e.

[0249] The same experiment with p-Cl-phenethylamine yielded a salt whichalso included all 3 acids (68% e.e.).

[0250] An experiment with 1.35 g (10 mmole) racemicp-CH₃-phenethylamine, 830 mg (5 mmole) R-(−)-p-CH₃-mandelic acid and 680mg (5 mmole) phenylacetic acid in 25 ml IPA yielded a salt containingboth acids and amine with 90% e.e.

[0251] An experiment with 1.35 g (10 mmole) racemic p-CH₃-phenethylamineand 1.66 g (10 mmole) R-(−)-p-CH₃-mandelic acid in 50 ml IPA yielded asalt with 57% e.e.

[0252] H. Resolution of Rac. Amines with Mixtures Containing ResolvingAgents with Opposite Configuration

EXAMPLE XXII

[0253] Resolution of the PEA I-mix (Ratio: 1:1:1) with SubstitutedMadelic Acids with Opposite Configuration

[0254] The results are summarized in Table 3. TABLE 3 exp. yield e.e.mix nr. resolv. Eq solvent salt amines 1 (S)-p-CH₃-MA ½ MeOH 28% 94%(R)-MA ½ 2 (S)-p-CH₃MA ½ MeOH 10% 80% (S)-MA ½

[0255] Exp. 1:

[0256] yield after recr. 12%

[0257] e.e. after recr. 99%

[0258] salt: p-CH₃-MA:MA =9:1

[0259] Exp. 2

[0260] salt: p-CH₃-MA:MA =4:1

EXAMPLE XXIII

[0261] Resolution of p-Me-PEA with Substituted Mandelic Acids withOpposite Configuration

[0262] The results are summarized in table 4. TABLE 4 exp. yield e.e.nr. resolv. Eq. solvent salt amine 1 (S)-p-CH₃-MA ½ MeOH 14% 87% (S)-MA½ 2 (S)-p-CH₃-MA ½ EtOH 14% 90% (R)-MA ½ 3 (S)-p-CH₃-MA ½ MeOH 10% 83%(rac)-MA ½

[0263] Exp. 1: salt p-CH₃-MA : MA =4:1

[0264] Exp. 2: salt p-CH₃-MA : MA =6:1

EXAMPLE XXIV

[0265] Resolutions of o-Cl PEA with Phosphoric Acids with OppositeConfiguration

[0266] The results are summarized in Table 5. TABLE 5 exp. e.e. nr.resolv. Eq solvent amine P₁; P₂ 1 (−)-P₁ ½ EtOH 67% 6:1 (−)-P₂ ½ 2(−)-P₁ ½ EtOH 70% 8:1 (+)-P₂ ½ 3 (−)-P₁ ½ EtOH 66% 6:1 rac-P₂ ½

[0267] I. Resolution (Via Inclusion) of 1-phenylethanol Using Mixturesof TADDOL Derivatives

EXAMPLE XXV

[0268](4R,5R)-2,2-dimethyl-α,α,α′,α′-tetraphenyl-1,3-dioxolan-4,5-dimethanol(TADDOL I),(4R,5R)-2,2-dimethyl-α,α,α′,α′-tetra(p-methoxyphenyl)-1,3-dioxolan-4,5-dimethanol(TADDOL II) and(4R,5R)-2,2-dimethyl-α,α,α′,α′-tetra(p-methylphenyl)-1,3-dioxolan-4,5-dimethanol(TADDOL III) were prepared according to literature.

[0269] To a mixture of TADDOL 1 (1.0 g) and TADDOL II (1.1 g) in 20 mlbenzene was added racemic 1-phenylethanol (PE) and the mixture wasevaporated. To the residue 50 ml hexane was added and the suspension wasstirred overnight. The precipitate was collected and ¹H NMR showed all 3components present in a 2:2:1 ratio (TADDOL I: TADDOL II:PE). Theenriched alcohol was isolated by distillation of the precipitate (0.1mmHg: 80° C.). HPLC (Chiralcel OD) showed 82% e.e.

[0270] J. Comparative Resolutions of α-methylphenylalanine Amide UsingP- and W-mix and Separate Components

EXAMPLE XXVI

[0271] Resolutions were on a 1 mmole scale in 2-butanone, using thegeneral procedure. Results are summarized in table 6. TABLE 6 Resolvingagent e.e. (%) P-mix 98 P1 55 P2 57 P3 33 W-mix 33 W1 — W2 16 W3 13

[0272] for HPLC see Example I.25.

[0273] K. The Attainment of a Constant Composition on RepetitiveCrystallization

EXAMPLE XXVII

[0274] To a solution of (−)-ephedrine (3.6 g) in 75 ml i-propanol wasadded a (+)-P-mix (5.1 g). The mixture was heated to reflux and cooledto RT. After one recrystallization from i-propanol a mixed salt wasobtained with a constant composition (ephedrine/phencyphos/chlocyphos;2:2:1), which did not change on repeated recrystallization fromi-propanol.

[0275] To a solution of 1.8 g (20 mmole) rac. 2-amino-1-butanol in amixture of 5 ml IPA and 30 ml 2-butanone was added 3.2 g (20 mmole)(−)-A mix and after heating to reflux a clear solution was obtained,which was allowed to cool to room temperature with stirring and after 3hours the mixed salt was collected. After one recrystallization from2-butanone the mixed salt had the same composition. (alcohol:M.A.:p-Me-M.A.=5:2:3).

[0276] L. Fast Screening of Resolving Agents

[0277] An equimolar mixture of 11 resolving acids (11-acid-mix)containing of: (−)-P1, (−)-P2, (−)-P3, (−)-W1, (−)-W2, (−)-W3, (−)-A1,(−)-A2, (−)-malic acid, (−)-phenylsuccinic acid and (+)-camphorsulphonicacid was used in Examples XXVIII and XXIX.

EXAMPLE XXVIII

[0278] 2.9 g (11 mmole) 11-acid-mix was dissolved in 80 ml IPA(isopropylamine) under reflux and 1.72 g (11 mmole) rac.2-chloro-α-phenetylamine was added to the hot solution. The mixture wasallowed to cool to room temperature under stirring and the salt wascollected after 18 hours. The salt composition was determined by ¹H NMR.The main components were the amine and the W1, W2 and W3 acids. The e.e.of the amine was 40% (HPLC). Recrystallization from IPA/MeOH (2:1) didnot change salt composition but e.e. increased to 84% (HPLC).

EXAMPLE XXIX

[0279] 2.9 g (11 mmole) 11-acid-mix was dissolved in 50 ml IPA underreflux and 1.5 g (11 mmole) rac. α-ethylbenzylamine was added.Crystallization started within 1 minute and the mixture was allowed tocool to room temperature under stirring. The salt was collected after 2hours and ¹H NMR showed that the salt consisted of the amine and acidsW1, W2 and W3. The e.e. of the amine was 10% by HPLC. The salt wasrecrystallized from 50 ml IPA+100 ml MeOH and the composition did notchange (¹H NMR) but e.e. of the amine increased to 22%.

[0280] Examples XXX-XXXII show fast screenings of resolving agentsaccording to the invention which result in a single resolving agent.

EXAMPLE XXX

[0281] Resolution of Racemic α-methyl-benzylamine with N-acetyl-L-aminoAcid-mix

[0282] a) To a solution of 1.25 g (10 mmol) of racemica-methyl-benzylamine in 10 ml of toluene, 3 ml of isopropanol and 1 dropof water, was added a mixture of 6 N-acetyl-L-amino acids (1.6 mmoleach).

[0283] The mix was prepared from the following L-amino acids: L-Phe,L-Tyr, L-Try, L-phenylglycine, L(+)-p-hydroxyphenylglycine andS-indoline-2-carboxylic acid.

[0284] The mixture was heated to reflux and the clear solution cooled toroom temperature. After stirring for 2 hours at room temperature theresulting solid was isolated, washed with 1 ml of toluene and dried,yielding 131 mg salt.

[0285] HPLC analysis showed salt formation with onlyN-acetyl-L-p-hydroxyphenylglycine. Chiral HPCL (Crownpack CR(−)) gavee.e. =62%.

[0286] b) Subsequently a mixture of 720 mg (6 mmol) racemicα-methylbenzylamine and 1.26 g N-acetyl-L-p-hydroxy-phenylglycine (6mmol) in 20 ml toluene, 20 ml isopropanol and 3 ml water was heated toreflux and the clear solution cooled to room temperature. After stirringfor 1 hour at room temperature the solid was isolated, washed with 2 mlof toluene and dried. 637 mg (32%) salt was obtained with e.e. =94%(chiral HPLC, Crownpack CR (−)).

EXAMPLE XXXI

[0287] Resolution of cis-1-aminoindan-2-ol with N-acetyl-L-amino AcidMix

[0288] a) 990 mg racemic cis-1-aminoindan-2-ol and the sameN-acetyl-L-amino acid-mix was used in Example XXX (1.6 mmol each) in 12ml 2-butanone and 3 ml Isopropanol was heated to reflux and cooled toroom temperature.

[0289] After stirring for 4 hours the resulting solid was isolated,washed with 1 ml of 2-butanone and dried, yielding 180 mg salt.

[0290] HPLC analysis of the salt showed the presence of onlyN-acetyl-S-indolinecarboxylic acid and an e.e. of 36% (Crownpack CR(−)).

[0291] b. Subsequently 500 mg racemic cis-1-aminoindan-2-ol and 648 mgN-acetyl-S-indolinecarboxylic acid in 30 ml 2-butanone and 5 drops ofwater were heated to reflux and the clear solution cooled to roomtemperature.

[0292] After stirring for 4 hours at roomtemperature the solid wasisolated, washed with 1 ml of 2-butanone and dried. 326 mg salt wasobtained (yield 29%).

[0293] The (−)-cis-1-aminoindan-2-ol had e.e. =98% (chiral HPLC,Crownpack CR (−)).

EXAMPLE XXXII

[0294] Resolution of dl-mandelic Acid with L-amino-acid-amide-mix

[0295] 910 mg (6 mmol) dl-mandelic acid, 160 mg NaOH-50% and a mix ofL-tyrosine amide, L-phenylalanine amide.HCl and L-phenylglycine amide (2mmol each) in 10 ml ethanol 96% was heated to reflux.

[0296] The clear solution was allowed to cool to room temperature.

[0297] After stirring for 1.5 hours the solid was isolated, washed with2 ml of ethanol 96% and dried.

[0298] The yield was 310 mg.

[0299] HPLC and ¹H NMR analysis showed a salt with only L-phenylglycineamide.

[0300] The mandelic acid was isolated via treatent with hydrochloricacid and extraction with toluene. After evaporation, the residue wassolved in 6 ml of water and the concentration of mandelic acid measuredwith HPLC.

[0301] The optical rotation of this solution was measured: [ ]_(D)=−146(25° C., c=0.47).

[0302] From this value an e.e. of 95% was calculated.

[0303] This provides us with a fast screening method for resolvingagents which in general will look like this:

[0304] Add a mix of resolving agents (for instance acids or amines) tothe racemate and determine the composition of the salt and the e.e. ofthe resolved enantiomer. If the e.e., even after recrystallisation froma suitable solvent, is good enough then look which resolving agent(s)is/are responsible for the resolution and use this/these in subsequentresolution experiment. If the e.e. is not acceptable, even afterrecrystallisation from a suitable solvent, than start a new experimentwithout the resolving agents present in the first salt. By repeatingthis sequence as a rule one will end up with an acceptable e.e. and asalt composition reflecting the resolving agent which can be used infurther resolutions, and can serve as a starting point for furtheroptimalisation.

1. Diastereomer complex comprising at least three compounds of which atleast one compound is a resolving agent in optically active form and atleast one compound is an enantiomer in optically active form. 2.Diastereomer complex according to claim 1 , where the complex is a salt.3. Diastereomer complex according to claim 1 or 2 which contains atleast two resolving agents in optically active form and at least oneenantiomer in optically active form.
 4. Diastereomer complex accordingto claim 1 or 2 which contains at least two enantiomers in opticallyactive form and at least one resolving agent in optically active form.5. Diastereomer complex according to any one of claims 1-4 whichcomprises at least three resolving agents in optically active form. 6.Diastereomer complex according to any one of claim 1 or 5 which containsat least three enantiomers in optically active form.
 7. Diastereomercomplex according to any one of claims 1-6, the enantiomer in opticallyactive form being a carboxylic acid, an amine, an alcohol, an aminoacid, an amino alcohol or a thiol.
 8. Diastereomer complex according toany one of claims 1-7, at least one enantiomer being present in anenantiomeric excess larger than 95%.
 9. Diastereomer complex accordingto any one of claims 1-8, the mixture(s) of enantiomers being chosenfrom one of the groups having formula E1 up to and including E21. 10.Diastereomer complex according to any one of claims 1-9, the resolvingagents being chosen from one of the groups having formula S1 up to andincluding S14.
 11. Process for the preparation of a diastereomer complexaccording to any one of claims 1-10 in which one or more mixtures ofenantiomers in a solvent are contacted with one or more resolvingagents, yielding the diastereomer complex.
 12. Process according toclaim 11 , in which more than one resolving agents are added. 13.Process according to claim 11 , in which individual agents are added oneafter the other without interim recovery of any solid formed. 14.Process according to claim 12 , in which the resolving agents are addedsimultaneously.
 15. Process according to any one of claims 11-14, inwhich (a mixture of) the enantiomer(s) present in the diastereomer aresubsequently isolated in optically active form from the diastereomercomplex.
 16. Agent for the separation of a mixture of enantiomerscomprising at least two resolving agents, of which at least oneresolving agent is in optically active form.
 17. Agent according toclaim 16 , the agent comprising at least three resolving agents, ofwhich at least two resolving agents are in optically active form.